PEGASIS (Pegasys)

  

       Synonym : Peginterferon alpha-2 (40 kDa), Peginterferon alfa-2a (40 KD)

       Expiry date : 2 years

       Storage conditions : In the dark place at a temperature of 2-8 ° C (not freezing)

   The composition and the form of output. 1 bottle with a single dose for subcutaneous injection contains : PEG- interferon alpha? 2 (40 kDa), 135 µ g / 1.0 ml, 180 ug / ml 1,0

   Fillers : sodium chloride, polisorbat 80, benzyl alcohol, sodium acetate, acetic acid, water for injection.

   Description. Transparent solution of colorless to light yellow.

   The drugs act. When PEG conjugation (bis monometoksipolietilenglikolya) with interferon alpha? 2 and interferon alpha pegilirovanny formed? 2. Interferon alpha? 2 is a biosinteticheskim method for recombinant DNA technology and is a derivative product of the gene cloned human leukocyte interferon and imposed ekspressiruyuschegosya in Escherichia coli cells. Structure of PEG direct impact on the clinical and pharmacological characteristics Pegasisa. In particular, the size and the degree of divergence PEG with molecular weight of 40 kDa identifies indicators intake, distribution and breeding Pegasisa.

   Mechanism of action. Interferon associated with specific receptors on the surface of cells, launches a complex intracellular signal mechanism and the rapid activation of gene transcription. Stimulated interferon genes modulate many biological effects, including suppression of virus replication in infected cells, the suppression of cell proliferation and immunomodulyatsiyu.

   The effectiveness. Clinical studies have demonstrated the effectiveness Pegasisa in the treatment of chronic hepatitis C patients, including those with compensated cirrhosis.

   Patients with liver cirrhosis. The study NV15495 adult patients with compensated chronic hepatitis C and the presence of HCV RNA, gistologicheski confirmed diagnosis of cancer or cancer beginning, have not previously received interferon treatment, the method of randomisation distributed in the treatment group or injections Roferona-A MED three 3 times a week, Pegasisa injections in a dose of 90 µ g 1 every week or dose of 180 ug 1 every week for 48 weeks, after which the patients seen during 6 months without treatment. The study included 271 patients (originally 72% of men, 88% of white and 78% with cirrhosis, 21% with effect from cirrhosis, 56% infected with genotype I).

   Patients with liver cirrhosis or without him. In two studies, and NV15496 NV15497-entered adult patients with compensated chronic hepatitis C, increased ALT, an antibody to hepatitis C virus, HCV RNA, had not previously received interferon.

   The study randomized patients NV15496 method of distributing the treatment or injections Roferona-A 3 MED three times a week or injections Pegasisa dose of 135 ug 1 every week or one dose of 180 µ g once a week for 48 weeks, after which patients watched over 6 months without treatment. The study included 639 patients (originally 68% of men, 86% of white and 18% with cirrhosis of the liver or cirrhosis beginning, the average index histology activity Knodellya 9, 66% infected with genotype 1).

   The study randomized patients NV15497 method of distributing the treatment or injections Roferona-A MED 3 to 6 times a week for 12 weeks, followed by 3 MED three times a week for 36 weeks or injections Pegasisa dose of 180 ug 1 every week; During the 48 weeks, after which the patients seen during 6 months without treatment. The study included 531 patients (originally 67% of men, 85% of white, 13% of cirrhosis of the liver or cirrhosis beginning, the average index histology activity Knodellya 9, 62% infected with genotype 1).

   The studies NV15496 and NV15497 treatment Pegasisom dose of 180 µ g of virus RNA was reduced to a level below the definition (less than 100 copies / ml, which is equivalent to 50 IU / ml; The definition of a device Amplikor HCV Monitor TM, Version 2.0) by 71 and 82% of patients, respectively. The study NV15495, where 78% of patients had liver cancer therapy Pegasisom dose of 180 µ g of viral RNA reduced to a level below the definition of the 55% of patients.

   For patients who have by the end of 12 weeks of therapy Pegasisom dose of 180 ug concentration of HCV RNA did not fall below the detection or is not reduced at least 2log10, achieving virologic remission for continuing treatment is unlikely. After virological results should decide on the abolition of therapy, as the frequency of virologic stable remission from Non responderov is less than 2%. But for some patients, especially those with cancer, can be justified continued treatment Pegasisom because histology answer could come in the absence of virologic remission (see Table. 2).

   Significantly, in clinical studies because of undesirable events in the first 12 weeks of therapy groups Pegasisa 180 ug who dropped only 3% of patients.

   In all studies, most of the patients receiving Pegasis, serum ALT activity returned to normal or decreased. However, ALT may not normal to complete the course of treatment Pegasisom, even in patients whose HCV RNA disappears.

   Regardless of the normalization of ALT, the concentration of viral RNA can better assess the effectiveness of treatment Pegasisom.

   Antibody to interferon. The studies NV15496 and NV15497 neutralizing antibodies to interferon degrees, respectively, only 1 to 2% of patients receiving Pegasis dose of 180 ug.

   Farmakodinamika. In healthy individuals around 3-6 h after a single subcutaneous injection Pegasisa activity 2 ', 5' - oligoadenilatsintetazy (2 ', 5' OAS, antivirus activity marker) in serum is growing rapidly. Increased activity whey 2 ', 5' OAS, created by Pegasisa remains more than one week and one after a single subcutaneous injection of interferon dose of 3 or 18 MED. For those over 62 years of amplitude and duration of activity of 2 ', 5' OAS after a single subcutaneous injection Pegasisa less than healthy persons younger.

   Pharmacokinetics. Pegasisa pharmacokinetic study of healthy volunteers and from those infected with hepatitis C virus

   Suction. Following a single subcutaneous injection of 180 µ g Pegasisa healthy individuals serum drug concentrations are determined within 3-6 hours After 24-48 h Whey concentration reaches 80% of the maximum. Suction Pegasisa long, Cmax serum there through 72-96 h after preparation. Absolute bioavailability Pegasisa is 84% and it is similar to interferon alpha? 2.

   Distribution. Pegasis found mainly in the blood and extracellular fluids. In humans, the amount of the distribution equilibrium state (Vss), after the on / in the introduction of 6-14 litres. According to the mass spectrometry and autoradiolyuminografii individual tissues and body, in rats Pegasis than stay in the blood in high concentrations into the fabric of the liver, kidney and bone marrow. After a single on / in a radioactively mechennogo Pegasisa of brain radioactivity than has pointed.

   Metabolism. Biotrasformatsiya is a key mechanism for clearance Pegasisa unchanged. Features metabolism Pegasisa not fully described, but the study in rats suggests that the main body of the withdrawal radioativno mechennogo drug or its metabolites are kidneys.

   Return. In humans, Cl system is approximately 100 ml / hour, which is 100 times lower than that of the original interferon alpha? 2. After the on / in a T1 / 2 Pegasisa terminal phase is about 60 h (with a standard interferon-3-4 h). After S / to a T1 / 2 terminal phase of longer-about 80 hours (range 50-140 h, most of the patients). T1 / 2 terminal phase after S / to the introduction may not reflect the withdrawal, as long suction Pegasisa.

   Entering Pegasisa 1 every week of healthy people and patients of chronic hepatitis C notes dozozavisimoe increase exposure to the drug.

   Patients who are chronic hepatitis C through 5-8 weeks Pegasisom therapy once a week Whey drug concentrations are 2-3 times higher than that after a single injection. After 8 weeks of treatment with a drug one time in weeks further cumulation is not happening. After 48 h treatment ratio of the maximum and minimum concentration of about 1,5-2,0. Pegasisa serum concentrations are maintained in a week (168 hours) after injection.

   Pharmacokinetics and farmakodinamika in special populations.

   Patients with kidney function violation. Pharmacokinetic data obtained from 23 individuals with Cl creatinine in the range of more than 100 ml / min (normal renal function) to 20 ml / min (expressed renal failure), have not revealed reliable relationship between pharmacokinetics and Pegasisa Cl creatinine. For those with most pronounced renal insufficiency Pegasis caused much less expressed increasing OAS. Effect of renal failure on the pharmacokinetics Pegasisa minimum.

   Portability Pegasisa and undesirable phenomenon after his single S / to a dose of 90 µ g of patients with kidney failure were the same as those of healthy individuals; Their frequency of renal failure increased slightly. Undesirable phenomena and laboratory anomalies noted in the study are consistent with those expected for the treatment of interferon (see "Precautions").

   Paul. Pharmacokinetic rates after a single S / Pegasisa introduction to healthy individuals of the female and male were comparable.

   Patients Elder. For those over 62 years after a single intake Pegasisa S / to a dose of 180 µ g was slow, but as long as that of healthy individuals younger (Tmax older-115 hrs, a young 82-hour). "The concentration-time area under the curve (AUC) increased moderately (1663 and 1295 h x ng / ml, respectively), but Cmax in the two age groups were similar (9.1 and 10.3 ng / ml). Based on exposure to the drug, farmakodinamicheskomu response and endurance, dose modification in patients age is not required (see "Method of treatment and dosing).

   Patients with cirrhosis and without cirrhosis. Pharmacokinetics Pegasisa from healthy individuals and patients with hepatitis C cases. For patients with compensated cirrhosis exposure to the drug and pharmacokinetic characteristics were similar to those in patients without cirrhosis.

   Indications. Treating patients with chronic hepatitis C with cirrhosis or compensated cirrhosis in adults.

   Method of application and dosing regime. Standard mode overdose

   The recommended dose is 180 µ g Pegasisa 1 every week p / to over 48 weeks.

   Specific guidance on dosing (dose modification)

   General. If the dose modification is required because of clinical or laboratory moderate and severe reactions, usually lower dose of 135 ug. However, in some cases, reduce the dose of 90 µ g or 45 µ g. After a side-reactions can consider reimposing increasing doses up to the old (see "Precautions" and "Undesirable events").

   Hematology. Reducing the dose recommended reducing the number of neutrophiles to less than 750 cells in 1 mm. Patients who are absolute number neutrophiles less than 500 cells in 1 mm before treatment should be interrupted as long as it does not exceed 1,000 cells in 1 mm. Application Pegasisa should resume at the dose of 90 µ g control of neutrophiles.

   Reducing the dose of 90 µ g recommended reducing the number of platelets less than 50,000 cells in 1 mm. Patients who are absolute number neutrophiles less than 25,000 cells in 1 mm product should be removed altogether.

   Associated with liver function. Patients who are chronic hepatitis C are also frequent fluctuations increased activity of functional liver samples. When treating Pegasisom, like other alpha interferon, including patients in virologic remission, ALT activity to increase over the original level. With progressive increase ALT, as compared to before treatment, the dose Pegasisa You must reduce to 90 ug. If ALT activity continues to grow, although at a lower dose, or by an increased concentration cium or signs of liver decompensation process, the preparation should be abolished.

   Special groups of patients.

   Renal failure. Patients with kidney function violation correction dose is not required. For patients requiring hemodialysis, the use Pegasisa not studied (see "Precautions").

   Liver failure. Judging from the data on the pharmacokinetics, portability and security, according to clinical studies, patients with cirrhosis (Class A on Child Pugh) correction dose is not required. For asthma patients with liver failure of Pegasisa not studied (see "Precautions").

   Children. The safety and effectiveness of drugs from persons under 18 years of age have not been established. Solution Pegasisa injection contains benzyl alcohol, so the drug should not appoint newborns and infants (see "Precautions").

   Patients age. Judging from the data on the pharmacokinetics and safety prerenosimosti obtained in clinical studies of patients age correct dose is not required.

   Contraindications. Increased sensitivity to alpha interferon, product life Escherichia coli, to polietilenglikolyu or any other component of the drug; Autoimmune hepatitis.

   Side Effects. When treating Pegasisom can expect the same adverse reactions have been observed with other alpha interferon.

   These clinical studies.

   The frequency and severity of the most common reactions in the treatment Pegasisom and interferon alpha? 2 and the same.

   The most common adverse reactions in the treatment Pegasisom dose of 180 ug were usually lightly or moderately and kupirovalis without dose adjustment or withdrawal of the drug.

   In clinical studies frequency lifting treatment in all patients due to undesirable phenomena and laboratory violations, was 10% as in the treatment of interferon, and Pegasisom. Laboratory rejection led to the cancellation Pegasisa only 2% of patients. Frequency lifting drugs in patients with cirrhosis was the same as in all patients as a whole.

   Adverse reactions encountered in treating Pegasisom with frequency? 2% but less than 10%, include fatigue, drowsiness, pain in the chest, grippopodobny syndrome was ill, tides, zyabkost breach memory parestezii breach of taste sensations, weakness, gipestezii, tremor, muscular convulsions, pain in the neck, dermatitis, increased sweating, rash, dry skin, night ports, the reaction photosensitization, dry mouth, bleeding gums, ulcerative stomatitis, anxiety, mood changes, reduced libido, anxiety, aggressiveness, lower body mass, cough, dyspnoea, pain, sore throat, nazofaringit , visual, inflammatory diseases of the eye, hypothyroidism, rapid heartbeat.

   In patients receiving Pegasis in clinical research, as with treatments for other interferon, described cases following undesirable phenomena : the effects on the liver, adipose liver dystrophy, holangit, notice, a violation of conduct, including suicidal spirit and traumas, diabetes, autoimmune phenomena , peripheral neuropathy, ulcer disease, gastrointestinal bleeding, reversible reaction from the pancreas (such as higher amylase and lipase activity without pain or pain), corneal ulcers, infections, endocarditis, pneumonia, interstitial pnevmonit fatal pulmonary embolisms artery coma, an overdose of drugs . In addition, the treatment described Pegasisom myofasciitis and bleeding in the brain.

   Laboratory performance.

   Hematology. Like other interferon treatment Pegasisom dose of 180 µ g associated with a decline in blood indicators, which tend to be improved after adjusting doses and returned to the original level within 4-8 weeks after the end of therapy (see "Precautions" and "Method Use ").

   Although treatment Pegasisom dose of 180 µ g accompanied by small gradual decrease in hemoglobin and gematokrita, dose modification on the anemia requiring less than 1% of patients, including with cirrhosis. Therapy Pegasisom accompanied by a decline in total leukocyte count, and the absolute number of neutrophiles. At one time or another therapy reduced the absolute number of neutrophiles to less than 500 cells in 1 mm was approximately 4% of patients. Application Pegasisa by fewer platelets. In clinical studies decline in the number of platelets to less than 50,000 cells in 1 mm was approximately 5% of patients, most often in patients with cirrhosis and platelets were idle about 75,000 cells in 1 mm.

   The function of the thyroid gland. Treatment Pegasisom accompanied clinically significant changes in laboratory indicators of thyroid function requiring clinical activities (see "Precautions"). The frequency of these changes was the same as in the treatment of other interferon.

       Precautions. Treatment Pegasisom be conducted under the supervision of a qualified doctor, because it can cause moderate or severe adverse events requiring dose reduction, a temporary interruption or complete cessation of therapy.

   For patients receiving interferon, incl. Pegasis, can develop serious psychiatric side-effects. In patients, as previously affected, and not suffering from mental illness may be depression, suicidal spirit and traumas. For patients with depression in the history Pegasis should be used with caution, the physician should monitor patients for signs of depression. Even before the Pegasisom treatment, physicians should inform patients of the possibility of depression, and patients should immediately inform the doctor of any sign of depression; In such cases, ask for assistance from a psychiatrist and consider whether to repeal therapy (see "Side Effects ").

   Treatment of interferon therapy, including Pegasisom can accompany cardiovascular reactions such as arterial hypertension, supraventrikulyarnye notice pain in the chest and myocardial infarction, and patients with heart disease should be appointed Pegasis with caution.

   The safety and effectiveness of Pegasisa asthma in patients with liver disease is unknown, therefore appoint medication to these patients is not recommended. Should the application Pegasisa develop signs of liver decompensation, it should be abolished. Patients who are receiving treatment Pegasisom, like other alpha interferon, including in patients in virologic remission, ALT activity to increase over the original level. If ALT activity continues to grow, although at a lower dose, or by an increased concentration cium or signs of liver decompensation in the process, the preparation should be abolished (see "Method of Use").

   As with other interferon, to be careful in appointing Pegasisa in combination with other potentially mielotoksichnymi drugs.

   Pegasis appointed with caution to patients with a baseline of less than 1,500 cells neutrophiles 1 cells, platelets less than 75,000 cells in 1 mm or a hemoglobin level less than 10 g / dl (see "Method of Use").

   Entering Pegasisa, and the introduction of cell protein can develop anafilaktoidnye reaction. In such cases, medication and cancel immediately appoint a pharmaceutical therapy.

   The drug is not intended for use in newborns and infants. An occasional deaths among newborns and infants associated with excessive exposure to benzyl alcohol. Number of benzyl alcohol, which is in newborns and infants phenomenon toxicity or side effects is not known (see "Method of Use").

   When treating alpha interferon described worsening autoimmune diseases, and in patients with such diseases Pegasis be applied with caution.

   When treating Pegasisom as interferon and other, cases and hypo giperglikemii.

   The use of alpha interferon accompanied worsening psoriasis. Psoriasis patients Pegasis should appoint cautious, but with worsening disease consider lifting the drug.

   During therapy Pegasisom, like other alpha interferon, described pulmonary symptoms, including dyspnoea, pulmonary infiltrates, pneumonia and pnevmonit, including fatal. If persistiruyuschih or accrual pulmonary infiltrates or drug violations lung function should be abolished.

   In rare cases after treatment of alpha interferon described ophthalmic pathology, including bleeding in the retina, cotton ekssudaty, Be'er retinal arteries or veins. Any patient, presenting complaints of the severity of deterioration or narrowing of the vision, go for eye examination.

   Laboratory testing. Before treatment Pegasisom all patients to undergo a standard general clinical and biochemical blood tests. In general therapy clinical blood tests should be repeated every 2 weeks, and biochemical every 4 weeks; Periodically for further analysis.

   Pegasis may be nominated in the laboratory following indicators : the number of platelets? 90000 cells in 1 mm (in patients with cirrhosis or cancer in shift-75000 cells in 1 mm), the absolute number of neutrophiles (ACHN)? 1500 cells in 1 mm, the level of serum creatinine less than 1.5 times the upper limit of the rules of TTG and T4 within the normal function of the thyroid gland or adequately controlled.

   Therapy Pegasisom accompanied decline as total leukocyte count, and ACHN that usually occurs in the first two weeks of therapy (see "Side Effects"). In clinical studies further lowering of standard elements are rarely observed. In ACHN decline to less than 750 cells in 1 mm to reduce the dose of the drug (see "Method of Use"). Patients who are less than 500 cells ACHN 1 mm product should be lifted before long as ACHN not rise to the level of more than 1,000 cells in 1 mm. In clinical studies Pegasisa decrease ACHN was reversible after dose reduction or withdrawal of the drug. Although rising temperatures may be due to flu syndrome, often observed in the face interferonoterapii, it is necessary to exclude other causes fever, especially in patients with neutropenia.

   Treatment Pegasisom accompanied decline in the number of platelets, which after treatment returned to the original (see "Side Effects"). By reducing the number of platelets to less than 50,000 cells in 1 mm to reduce the dose of drug, but at a lower level to 25,000 cells in 1 mm-lift product (see "Method of Use").

   When treating alpha interferon, including Pegasis, described as a violation of the thyroid gland or a deterioration of thyroid diseases. If violations of thyroid function are not adequate correction to cancel product.

   As with other alpha interferon treatment, some patients during therapy Pegasisom was expressed increased serum triglycerides. Before correct dose, it is necessary to start up or dietary medicinal therapy, given the concentration of triglycerides shock. After lifting Pegasisa gipertriglitseridemiya quickly.

   Pregnancy and lactation.

   The impact on fertility Pegasisa not been studied. In appointing PEG- interferon alpha? 2, and other alpha interferon, uses monkeys was lengthening their menstrual cycle, accompanied by a decline and a later transition to high concentrations of beta 17 seconds and progesterone. When the drug normal menstrual cycle.

   Impact PEG- interferon alpha? 2, and the fertility of men had been studied. However, the introduction of interferon alpha? 2 and in doses up to 25.106 MED / kg / day for 5 months had no effect on male fertility makak- Rh.

   Teratogenic Effects Pegasisa not studied. The use of interferon alpha? 2 resulted in a reliable increase in spontaneous abortions among makak- Rh. There offspring born in time, no teratogenic effects were observed. However, the treatment Pegasisom, like other alpha interferon, women of childbearing age should recommend effective methods of contraception.

   The safety of drugs in pregnancy in humans has not been established, so Pegasis should be appointed only if potential benefits for the mother than the potential risk to the fetus.

   It is not displayed or whether Pegasis components drug with breast milk. Since breast milk removed many of the drugs, be careful in appointing Pegasisa nursing mothers. Impact Pegasisa caught in the body of an infant oral mother, was not investigated.

   The impact on the ability to drive a car or work with machines and tools

   Patients who have developed dizziness, drowsiness, sputannost consciousness and weakness, warning against driving a car or work with machines and tools.

       Interaction. In ongoing clinical studies of combination therapy Pegasisom ribavirin and no pharmacokinetic interactions between these drugs are not mentioned.

   Alpha interferon may affect the processes of oxidative metabolism, reducing the activity of liver enzymes mikrosomalnoy system tsitohroma P450. However, healthy men p / Pegasisa to a dose of 180 ug 1 every week over four weeks does not have any impact on the pharmacokinetics mefenitoina, dapsone, and debrizohina tolbutamida; Therefore, healthy men Pegasisom treatment does not affect the metabolic activity in vivo izofermentov system tsitohroma P4503A4, 2C9, 2C19 and 2D6.

   The same study indicated an increase in the area under the concentration-time curve, "teofillina (AUC), a marker of activity izofermenta 1 A2 tsitohroma P450, about 25%. Pegasis is moderate inhibitor activity izofermenta 1 A2 tsitohroma P450. For patients receiving both Theophylline and Pegasis, teofillina to control concentrations in serum and implement appropriate corrective doses teofillina.

       Overdosing. An overdose cases Pegasisa, introducing drug within 2 days (without week interval), and a daily for a week (total dose of 1260 µ g / week). No unusual, and serious impact on the treatment of unwanted phenomena has been none of these patients. In clinical studies with cancer and chronic kidney mieloleykoze drug injected in doses up to 540 and 630 ug per week. No signs of toxicity, further restricting the use of these doses were weak, increasing liver enzymes and neutropenia, which may occur with conventional interferon treatment.

       Specific instructions. Treatment with drugs

   Before the introduction of intravenous drugs, which was a production and packaging, should be examined for foreign and change color.

   If the product is out, the patient must give resistant to stitch needle container for the storage of used syringes and needles. Patients should be carefully instructed in the importance of proper storage and disposal of materials used and warned against any re-use of needles and syringes. Completed container should be destroyed in accordance with the instructions of the doctor.

   Incompatibility.

   Pegasis not be confused with other drugs.

       Product and packaging. Bottles with a single dose of 135 µ g; 1 or 4 feet in the package.

   Bottles with a single dose of 180 µ g; 1 or 4 feet in the package.

       The expiry date. 2. The drug should not be used after this date marked on the package.

       Storage conditions. In the refrigerator at a temperature of 2-8 ° C, in the dark place. Do not freeze, not shaking. Keep out of reach of children.

       Conditions leave from pharmacies. On doctor's prescription.

       Producer. F. " Hoffmann- La Roche Ltd. "Switzerland.

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